1. Myeloma and Renal Disease
Paul Cockwell
Consultant Physician and Nephrologist, Clinical Lead Renal Medicine, Department of Nephrology, Queen Elizabeth Hospital Birmingham.
Hon Senior Research Fellow, University of Birmingham.

2. The stages of Chronic Kidney Disease
750
0.15
<15
Kidney Failure 5
1,500
0.3
15-29
Severe decrease in GFR 4
22,500
4.5
30-59
Mild-moderate decrease in GFR
3A&B
15,000
3.0
60-89
Maintained eGFR + other evidence of kidney damage 2
16,500
3.3
>90
normal or increased
GFR with evidence of kidney damage 1
No in UBC (estimate)
Prevalence
(%)
eGFR
ml/min/
1.73m2
Description
Stage*
The stages of Chronic Kidney Disease

3. Calculating estimated GFR
The different equations used for calculating estimated (e)GFR are not equivalent
aMDRD – current internationally accepted standard for reporting kidney function when the eGFR is abnormal
aMDRD factors 4 variables – age, sex, ethnicity and creatinine – to provide an eGFR
CG eGFR – the equation used in most drug dose adjustment algorithms in renal disease
CG and eGFR are not equivalent
aMDRD: abbreviated modification of diet in renal disease; CG: Cockcroft-Gault; (e)GFR: (estimated) glomerular filtration

4. Acute Kidney Injury Network (AKIN) staging
Only one criterion is required to qualify for stage
Stage
Serum creatinine criteria
Urine output criteria
Stage 1
Increased serum creatinine of ≥0.3 mg/dL (≥26.4 μmol/L) or ≥1.5-2 times from baseline
<0.5 mL/kg/ hour for >6 hours
Stage 2
Increased serum creatinine to ≥2-3 times from baseline
<0.5 mL/kg/ hour for >12 hours
Stage 3
Increased serum creatinine to >3 times from baseline
or ≥4.0 mg/dL (≥354 μmol/L) with an acute increase of at least 0.5mg/dL (44 μmol/L)
or renal replacement therapy
<0.3 mL/kg/ hour for 24 hours or anuria for 12 hours
Mehta RL et al. Crit Care 2007; 11: 1 – 8

5. Multiple myeloma
Renal function a major determinant of Morbidity/Mortality
Around 50% have significant renal impairment at presentation
At new presentation around 4 pmp require dialysis
Myeloma and dialysis survival poor

6. Disease specific kidney injury in Myeloma
Cast Nephropathy (Myeloma Kidney)
Tubular epithelial cell injury +/- interstitial inflammation and fibrosis
AL Amyloidosis
Light Chain Deposition Disease
Fibrillary GN
Heavy Chain Deposition Disease
Cryoglobulinaemic glomerulonephritis

7. Co-factors for Acute Kidney Injury in Myeloma
Drugs
NSAIDS
Diuretics
Hypercalcaemia
Sepsis
Volume depletion/dehydration
Operative stress

8. Disease specific kidney injury in Myeloma
Cast Nephropathy (Myeloma Kidney)
Tubular epithelial cell injury +/- interstitial inflammation and fibrosis
AL Amyloidosis
Light Chain Deposition Disease
Heavy Chain Deposition Disease
Cryoglobulinaemic glomerulonephritis

9. Intact Ig and Ig Free light chain (FLC) production by plasma cells
Lambda
- Dimeric
- 45 kd
- 20% renal clearance
- 4-6 hr serum half life
Kappa
- Monomeric kd
- 40% renal clearance
- 2-3 hr serum half life

10. Normal range – serum FLC
Lancet 2003; 361: 10

11. Immunoglobulin FLC levels in myeloma
k FLC (mg/L)
l FLC (mg/L)
Blood.2001: 97:
Immunoglobulin FLC levels in myeloma

12. Comprehensive Clinical Nephrology (Johnson & Feehally); p238

14. Rapid renal scarring in Myeloma Kidney Basnayake et al: J Clin Path
Presentation Biopsy
Repeat Biopsy
6 weeks
Basnayake et al: J Clin Path

15. NDT 2010: 25:

16. Severe AKI and myeloma is a medical emergency

17. Approach to AKI and suspected cast nephropathy
Screen ASAP with SPE and sFLC or UPE
Suspect cast nephropathy if sFLC>500mg/l or UPE BJP+ve
High quality supportive care
Prompt commencement of chemotherapy

18. Supportive Care Optimise urine output Correct hypercalcaemia
Correct acidosis
Avoid diuretics
Avoid nephrotoxic drugs

19. Chemotherapy Start ASAP Use dexamethasone and novel agents
There is increasing experience in bortezomib in severe renal failure

20. Early sFLC responses are a major determinant of renal recovery

21. 39 patients with cast nephropathy: Birmingham + Mayo
Renal recovery from cast nephropathy and changes in sFLC levels in the first 21 days
For an 80% chance of renal recovery there must be a 60% reduction in sFLC by day 21
39 patients with cast nephropathy: Birmingham + Mayo

22. What about extra-corporeal removal of FLC?

23. Plasma exchange can remove intravascular FLC
But does this translate into clinical benefit??

24. Plasma Exchange When Myeloma Presents as Acute Renal Failure A Randomized, Controlled Trial. Clark et al: Ann Intern Med. 2005;143:

25. MERIT – primary end-point (thanks to J Behrens and M Drayson)

26. ~15%
~ 85%
Myeloma Load
- FLC generation
intravascular
extravascular

27. Does High Cut-Off (protein-permeable) dialysis provide an alternative approach to plasma exchange for the removal of FLC?

28. Convective permeability
HCO Membrane - increased permeability for mid-molecules
Convective permeability

29. Gambro HCO 1100 –6 hour dialysis – FLC removal kinetics – myeloma patient
Serum free lambda (mg/L)
Lambda in dialysate (mg/L)
Time (mins)

30. Refractory Myeloma and Acute Renal Failure – recovery from dialysis30

31. Renal recovery rates in study population and
a case matched control population (P<0.001)
17 Control patients
17 Study patients
Hutchison et al, EDTA 2008.

32. Survival relates to recovery of renal function
Renal recovery (n-14)
P<0.001
No renal recovery (n-5)
Hutchison et al, cJASN 2009

34. EuLITE study design 90 Patient recruitment target Randomisation
Control Arm HD
45 Patients
Standard high-flux HD
Research Arm HD
45 Patients
Extended HD on HCO 1100
‘Modified PAD regimen’ Chemotherapy
(P) VELCADE™ (bortezomib) iv 1.0 mg/m2
(A) Adriamycin (Doxorubicin) iv 9.0 mg/m2
(D) Dexamethasone oral 40 mg
primary outcome = independence of dialysis at 3 months

35. Ideal timelines – personal view
Patient identified as at risk (AKI – unknown cause)
SPE and sFLC – urgent (same day)
Renal Biopsy if clinically suitable – urgent report
Urgent marrow if indicated by SPE/sFLC/Renal Biopsy
Immediate commencement of Dexamethasone followed by prompt addition of novel agent (e.g. Bortezomib)

36. Determinants of recovery from dialysis dependent renal failure: an international study

37. AKI secondary to cast nephropathy is a medical emergency analogous to RPGN secondary to vasculitis

39. Conclusions
Cast nephropathy secondary to myeloma and AKI is a medical emergency
Coordinated MDT working is required to optimise patient outcome
Early responses in serum FLC are required for a renal recovery
Effective chemotherapy is essential
The role of extra-corporeal removal of FLC is under evaluation

40. Acknowledgements
University Hospital Birmingham:
Colin Hutchison, Mark Cook, Lesley Fifer, Koli Basnayake, Steph Stringer, Consultant Nephrologists
Binding Site (University of Birmingham):
Jo Bradwell, Graham Mead, Stephen Harding
Gambro-Hechingen: Markus Storr; Hermann Goehl; Ulrike Haug; Werner Beck
Gambro-Lund: Andrew Gill
Tubingen: Nils Heyne; Katja Weisel
OrthoBiotech: Rod Murphy; Caroline Stanton, Paula Stubbs
Conficts of interests: Gambro; The Binding Site; OrthoBiotech